Catalytic cleavage of the androgen regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia

We identified TMPRSS2 as a gene that is down-regulated in androgen-ndepende nt prostate cancer xenograft tissue derived from a bone metastasis, Using s pecific monoclonal antibodies, we show that the TMPRSS2 encoded serine prot ease is expressed as a M-r 70,000 full-length form and a cleaved M(r)32,000 protease domain. Mutation of Ser-441 in the catalytic triad shows that the proteolytic cleavage is dependent on catalytic activity, suggesting that i t occurs as a result of autocleavage, Mutational analysis reveals the cleav age site to be at Arg-255, A consequence of autocatalytic cleavage is the s ecretion of the protease domain into the media by TiMPRSS2-expressing prost ate cancer cells and into the sera of prostate tumor-bearing mice. Immunohi stochemical analysis of clinical specimens demonstrates the highest express ion of TMPSS2 at the apical side of prostate and prostate cancer secretory epithelia and within the lumen of the glands. Similar luminal staining was detected in colon cancer samples. Expression was also seen in colon and pan creas, with little to no expression detected in seven additional normal tis sues, These data demonstrate that TMPRSS2 is a secreted protease that is hi ghly expressed in prostate and prostate cancer, making it a potential targe t for cancer therapy and diagnosis.